New Study Links Mystery Mutations to Kidney Disease, Unlocking Potential Therapies

The human genome is full of mutations associated with different diseases, but we don’t know what over 90 percent of those mutations do, as they reside in regions of non-coding DNA, formerly known as junk DNA. Using kidney disease as a proof of concept, a study published in Science describes a new way to link those mystery mutations to their biological functions, which could unlock our ability to understand and cure disease.

The study, which was led by Katalin Susztak, MD, PhD, professor of Medicine at the University of Pennsylvania Perelman School of Medicine, and Hongbo Liu, PhD, assistant professor in the Department of Biomedical Genetics at the University of Rochester Medical Center, focused on identifying genes that cause kidney disease. The team pooled 32 different types of genetic information to home in on a set of genes that are likely to cause kidney disease, as well as potential new drug targets to treat kidney disease.

Until now, it has been very difficult to tie mutations in non-coding DNA to cellular function. Non-coding DNA does not code for proteins, the molecules that carry out cell functions, but is involved in regulating how genes are expressed. The trouble is that we don’t know how this works.

Hongbo Liu, PhD

“Think about our genome as a bunch of noodles,” said Liu. “Noodles easily fold, so different parts of the noodle—or DNA—can interact. So, mutations in areas of non-coding DNA can interact with protein-coding genes that are far away. This makes it very challenging to identify which genes are targeted by each mutation. In our paper we provide a solution to this problem.”

The team analyzed DNA sequences of 2.2 million people and found over 1,000 locations in the genome that are associated with kidney function and disease. They then analyzed more than 700 human kidney samples and 237,000 kidney cells to understand how these mutations affect gene regulatory elements and how they impact gene expression.

By relating different types of genomic data to each other, they were able to create a “Kidney Disease Genetic Scorecard” that highlights genes and cell types that are likely to cause kidney disease, opening up new possibilities for therapies.

“This paper solves a vexing puzzle that has plagued genetic research for decades,” said Hartmut “Hucky” Land, PhD, the Robert and Dorothy Markin Professor and Chair of Biomedical Genetics at URMC, who was not involved in the research. “Not only does this study advance kidney disease, but the underlying principle shown here can be applied to many diseases.”